Welcome to the Harvard South Shore Psychiatry Residency 2020 Virtual Research Day.

May 06, 2020 marks the annual HSS Research Day, and our first HSS Research Day conducted virtually.

Celebration of resident and faculty scholarship and achievement has been a cornerstone of the culture we share at HSS, and this is exemplified in HSS Research Day. Residents, faculty, and staff come together to share their exciting work and to encourage each other in scholarly pursuit. The HSS community looks forward to this celebration as a yearly event, in conjunction with Harvard Mysell Day, at which residents from all Harvard-affiliated psychiatry programs come together to celebrate scholarship.

This year, both HSS Research Day and Harvard Mysell day were canceled. In this way, even our scholarly work has been indelibly marked by the COVID-19 pandemic. At a time in which we must remain physically distant for safety, it is all the more imperative that we preserve our shared culture at HSS, and maintain our social and scholarly connectedness. Thus the idea for HSS Virtual Research Day was born, so that members of the HSS family could continue to cheer each other on in academic pursuit.

​Our day features an opening keynote address by Dr. James Timothy McKenna, PhD, an accomplished neuroscience researcher and assistant professor of psychiatry at Harvard Medical School. Our day includes nine oral presentations, eight of which are delivered by resident physicians. The day features a total of twenty posters; although this does not reflect the full extent of research at HSS (as evidenced by our residents and faculty presenting at APA, AACAP, and other national meetings), it does reflect the curiosity and excitement that permeates our residents, faculty, and staff. Our day will end with a closing keynote address from Dr. Margo Funk, MD, MA, program director of Harvard South Shore Psychiatry Residency.

We welcome you to join us in celebrating scholarship and celebrating our community at HSS 2020 Virtual Research Day.

Dr. James Timothy McKenna, PhD​I am presently an Assistant Professor in the Department of Psychiatry at Harvard Medical School, Research Health Scientist at the VA Boston Healthcare System, and Director of the Neuroanatomy Section of the Laboratories of Neuroscience at the VA Boston Healthcare System. My research investigates sleep-wake regulation and disorders in rodent models, employing neuroanatomical, neurochemical/pharmacological, electrophysiological, optogenetic, and behavioral methods.

Research Highlights:

Neuroanatomical investigations of brain circuitry involved in modulation of the hippocampal EEG: My first experience conducting research was as a graduate student at Florida Atlantic University, under the mentorship of Dr. Robert P. Vertes. The oscillatory EEG theta rhythm of the hippocampus serves a major role in memory processing. These theta rhythms are generated by ascending neural circuitry, including the midline thalamus, medial septum, and mammillary nuclei. Employing retrograde tracer techniques (Fluorogold, Fluororuby), we reported single and collateral neural projections from the supramammillary nucleus to both the medial septum (the “pacemaker” of theta rhythms) and hippocampus in the rat (Vertes and McKenna, 2000). Our findings suggested that the supramammillary nucleus may play a select role in hippocampal theta generation by means of the described circuitry. Employing these same techniques, we described ascending neural projections from the brainstem median raphe nucleus to the medial septum and hippocampus (McKenna and Vertes, 2001). Of particular interest, the median raphe nucleus, a largely serotonergic region, may block theta generation and maintenance by means of the pathways described. A third study was an extensive examination of all projections to the nucleus reuniens of the midline thalamus, including input originating from numerous brain nuclei involving both sensory and limbic input, which may also play a role in theta-related neural activity (McKenna and Vertes, 2004). Abnormalities in theta-related circuitry have been shown in select brain disorders that report aberrant cognitive processing; for example, medial septum cholinergic dysfunction in Alzheimer’s disease. Therefore, further understanding of this circuitry may inform targeted therapeutic treatment to alleviate memory dysfunction seen in such disorders.

Neurochemical and electrophysiological investigations of the endogenous purine adenosine and its role in promotion of sleep: Following graduation, I pursued my post-doctoral studies in the laboratory of Drs. Robert McCarley and Robert Strecker. The laboratory had recently discovered that the endogenous neuromodulatory purine adenosine promotes the propensity to sleep (sleepiness) by means of inhibition of arousal-related nuclei in the brain, particularly in the cortex and the subcortical basal forebrain, an area which plays a major role in arousal, attention, and sleep/wake regulation. In one study, adenosine levels were measured in the rat basal forebrain using microdialysis/HPLC analysis techniques, which revealed a diurnal rhythm in which adenosine levels rise during natural wakefulness, and fall during sleep (McKenna et al., 2003). Furthermore, sleep disruption (modeling that seen in insomnia and apnea) produced elevated levels of adenosine in the basal forebrain (McKenna et al., 2003, 2007). In another study, neuronal activation demonstrated with an immunohistochemical label for cFos (an immediate early gene protein) was particularly noted in cholinergic basal forebrain neurons following sleep deprivation, as well as spontaneous wakefulness (McKenna et al., 2009). These studies suggest that, as wakefulness progresses, cholinergic basal forebrain neurons are active, promoting the release of adenosine, which in turn acts as an inhibitory modulator that induces sleepiness. This accumulation of adenosine in the basal forebrain may be the mechanism by which sleep disruption leads to excessive daytime sleepiness, observed in a number of clinical disorders including insomnia and obstructive sleep apnea.

Validation of novel genetic animal models to study GABAergic and glutamatergic neurons controlling behavioral state and EEG rhythms: Until recently, GABAergic and glutamatergic systems were largely overlooked as players in regulation of sleep-wake states, as well as a general role in brain arousal and cognitive systems, due to difficulty in identification with immunohistochemical techniques. Our laboratory has recently been evaluating the role that select GABAergic and glutamatergic populations may play in sleep-wake regulation, using genetic mouse models. Identification and further understanding of these neuronal populations will bolster development of pharmacotherapy to treat both sleep disorders and psychopathologies involving altered cognition.

For example, in one study (McKenna et al., 2012), we validated a novel mouse model in which green fluorescent protein (GFP) was genetically “knocked-in”, so that GFP specifically labeled GABAergic neurons (GAD67-GFP knock-in mice). GFP was selective to GABAergic neurons in both the brainstem subcoeruleus nucleus (a chief player in REM sleep phenomena; Brown et al., 2008) and the basal forebrain (McKenna et al., 2012). A large percentage of basal forebrain GABAergic neurons were identified to be co-labeled with parvalbumin (PV), a calcium binding protein, later demonstrated to play a unique role in brain arousal systems (Kim, Thankachan, et al., 2015; see below). Dr. Ritchie Brown and I collaborated on a review of GABAergic mechanisms in brain disinhibitory circuits, such as the basal forebrain-to-cortex GABAergic/PV projection crucial for cortical wake-related activation (Brown and McKenna, 2015).

Our new investigations aim to describe the anatomy, physiology, and functional role of basal forebrain glutamatergic neurons, using a vGluT2-tdTomato mouse model. Our recent study provides a comprehensive neuroanatomical description of vGluT2+ neurons in the mouse basal forebrain (McKenna et al., in preparation). These vGluT2+ neurons are a distinct population of neurons, and largely separate of cholinergic and GABAergic basal forebrain populations. The calcium binding proteins calbindin and calretinin, but rarely PV, were co-localized to a relatively small percentage of vGluT2+ basal forebrain neurons. Our cell-specific conditional anterograde investigation suggests that the basal forebrain glutamatergic population is uniquely positioned to serve a crucial role in integration of arousal in response to incoming stimuli, including a strong reward/learning component.

Evaluation of animal models of sleep disorders, including insomnia and obstructive sleep apnea: Another line of laboratory investigation is the development and validation of animal models of sleep disorders, such as obstructive sleep apnea and insomnia. Sleep apnea is a disorder that afflicts 7% of the adult population, with sleepiness, cognitive impairment and cardiovascular consequences. The laboratory has developed animal models of sleep apnea characteristics, including hypoxia (low oxygen levels), hypercapnia (high carbon dioxide levels), and sleep fragmentation. These studies were extended into a National Research Service Award (NIH), in which sleep fragmentation, mimicking that seen in the apneic patient, produced excessive sleepiness and cognitive impairment. Sleep fragmentation produced a rise of adenosine levels in the wake-promoting basal forebrain, providing a mechanism whereby sleep disruption leads to sleepiness (McKenna et al., 2007). A novel rodent model of the multiple sleep latencies test (mimicking the human diagnostic tool) was also developed to objectively measure sleepiness produced by our rodent sleep disruption models (McKenna et al., 2008).

Evaluation of the role of basal forebrain parvalbumin neurons in the promotion of arousal and cortical EEG gamma band oscillations: Cortical gamma band oscillations (GBO, 30-80 Hz) are involved in higher cognitive functions such as attention and working memory, and GBO abnormalities are seen in select neuropsychiatric disorders, including schizophrenia, bipolar disorder, and Alzheimer’s disease. These studies employed optogenetic techniques to selectively activate or inhibit the basal forebrain PV neuronal subpopulation, in order to investigate the role that these neurons may play in promotion of GBO (Kim, Thankachan, et al., 2015). We demonstrated that optogenetic activation of basal forebrain PV neurons strongly promoted GBO, largely by means of synchronization of the cortical GABAergic/glutamatergic circuitry responsible for GBO generation and maintenance. We therefore identified a possible target for treatment of related neuropsychiatric disorders. Furthermore, in a recently accepted manuscript (McKenna, Thankachan, et al., 2020), we provide functional evidence that basal forebrain PV neurons play a major role in mediating brief arousals from sleep in response to hypercarbia (similar to that experienced in apnea) and other sensory stimuli (sound). Our findings suggest that basal forebrain PV neurons may be involved in promotion of brief arousals from sleep in response to stimuli which may indicate physiological dysfunction or danger to the organism.

I have taught students and peers across many academic levels as a classroom instructor and bench scientist, from undergraduates to post-doctoral candidates. Presently, my educational contributions include lectures and course direction at Harvard Medical School, the VA Boston Healthcare System, as well as national society conferences. Furthermore, I have been quite involved in our laboratory internship program, hosting undergraduate students from two local colleges. As an academic, I have authored book chapters, reviews, and editorials, including extensive reviews of sleep/wake neural regulation such as our laboratory’s highly regarded publication in “Physiological Reviews” (Brown et al., 2013; ~870 citations, Google Scholar as of April 30, 2020).

I am presently a faculty member and lecturer for the Harvard South Shore Psychiatry Residency Training Program. I serve as the director of the PGY-1 course “Psychopathology”. I provide neurobiological review aimed to increase understanding of the underlying neural mechanisms, as well as pharmacotherapeutic treatment, of psychiatric disorders. I am also co-course director and instructor in the PGY-4 “Pop Neuroscience” didactic class. This course aims to increase critical thinking skills, involving objective evaluation of reported neuroscience news and primary source scientific sources. Furthermore, the course promotes effective communication skills, modeled in the class with physician/patient role playing. I was pleasantly surprised that, at the conclusion of the 2018-2019 academic year, I was recognized with a teaching award by the PGY4 program residents.

Laboratory Instruction:Outside of formal classroom teaching, I have served as an instructor to faculty in our department (including post-docs) and consulted for investigators at both the medical school as well as other institutions. Our laboratory established in the last decade a very successful undergraduate internship program, recently reviewed in the Journal of Undergraduate Neuroscience Education (McCoy et al., 2019). Our student interns come to the laboratory with some expertise developed during college laboratory courses, and, upon completion, are quite adept in techniques used in rodent neuroanatomical and behavioral investigations. I have mentored numerous undergraduate interns through the years now, some of whom have been authors on local and national conference presentations and publications. I served as a thesis advisor for one student from Wheaton College who received a Fulbright Scholarship based on her undergraduate academic and laboratory studies. Many of my interns have continued to graduate and medical school programs, pharmaceutical and biotechnology industry employment, and some now even serve as faculty in university programs.

Service:I have served locally on our institutional (VA Boston Healthcare System) Research Safety, Research and Development, and Institutional Animal Care and Use (IACUC) Committees. I previously served as Chair-Elect and Chair of the IACUC. Nationally, I have been quite involved in the Sleep Research Society, as a member of the Educational Programs, Board Nominating, and Membership committees through the years, and I am presently the Chair of the Membership committee. I have served as a reviewer for numerous journals and grant mechanisms, and I am presently a Review Editor for “Frontiers in Neurology”. I have served as an abstract, symposia, and post-graduate course reviewer for the Association of Professional Sleep Societies (APSS) yearly “Sleep” national meeting, and previously chaired an all-day post-graduate course at the meeting.

Summary:Study of behavioral state regulation and arousal systems is rapidly expanding, as loss of sleep has become increasingly recognized as a major health issue and is co-morbid with many neuropsychiatric disorders. This research provides a basis for the understanding of sleep-wake neural regulation, human sleep disorders, as well as cognitive dysfunction seen in select psychopathologies. I bring to teaching a passion and advanced knowledge of the subject matter of neuroscience, and aim to continue and improve the laboratory experiences of my interns.